Acamprosate (acetyl homotaurinate) is a pharmacological agent which has shown efficacy in the treatment of alcoholism. It is expected that this drug will be approved in the United States in the near future for this indication, and a number of clinical trials assessing further the efficacy of this compound are currently underway in this country. Preclinical studies have provided evidence that acamprosate decreases alcohol intake, preference for alcohol over water, and withdrawal symptoms during abstinence in rodent models. Clinical trials have shown that acamprosate significantly increases abstinence rates and clinic attendance days in detoxified alcoholics for periods up to one year. Despite its demonstrated clinical efficacy, no controlled laboratory studies to date have examined the underlying behavioral or neurochemical mechanisms of action in humans. This project proposes to evaluate systematically the effects of acamprosate on the direct pharmacodynamic effects of alcohol, alcohol craving, and alcohol self-administration across a broad dose range for both drugs. Specifically, the first study will assess the effects of acamprosate on the direct pharmacodynamic effects of alcohol. The second study will assess the effects of acamprosate on alcohol self-administration. In both studies, effects of acamprosate on alcohol craving will be determined. These laboratory studies will be conducted under rigorously controlled double-blind conditions using heavy drinking male and female volunteers and a within-subjects design. Results will elucidate the behavioral mechanisms of action of acamprosate, and will provide important information on the properties of acamprosate relevant to its clinical utility, efficacy, and safety. In addition, the illumination of the behavioral mechanisms involved in acamprosate effects may steer further examination of the pharmacological mechanisms of action, and help to guide development of additional pharmacotherapies for alcoholism that focus more strongly on these relevant mechanisms. More generally, these studies will enhance our understanding of alcoholism and the factors that influence treatment efficacy.